RE: [NMusers] NONMEM Modeling of Plasma + Urine Data

Hi Tarek,
 
I am assuming that the drug is given as an infusion from the "RATE" column
in your data file. You mentioned that you ran the model with just the
parent & metabolite data in plasma. Did you use ADVAN7 for that as well?
The formation of metabolite is not well defined..Is it a saturable process?
If so, Km and Vmax should be implemented.
 
Also, TVCL is total clearance as shown below:
TVCL = THETA(1)

CL = TVCL*EXP(ETA(1)) So, it is not clear how the following is implemented..

TVCLM = THETA(5)

CLM = TVCLM * EXP(ETA(5))

Usually Total Clearance is modeled as CL=CLRenal + CLMetab

Just quickly browsing through the data I do not see rate being declared in
your control file as R1=RATE. Curious about how the RATE was specified in
the control file when the parent & metab concentration in plasma was
modeled. I also see that V1 and V3 was scaled but not V2.
 
Your error structure is quite complex. It is not clear to me what the
purpose of ERR(4) is. Also your initial conditions for SIGMA seems to be
very high!
 
Typically the ERROR could be modeled as (There are many ways to do this..).
 
I1=0
I2=0
I3=0
I4=0
 
IF (CMT.EQ.1) I1=1
IF (CMT.EQ.3) I2=1
IF (CMT.EQ.4) I3=1
IF (CMT.EQ.5) I4=1
 
Y=IPRED + I1*ERR(1) + I2*ERR(2) + I3*ERR(3) + I4*ERR(4)
 
Instead of just additive model, did you try other ERROR models for e.g.
ADD+PROP etc?
 
Hope this helps.
 
Partha

-----Original Message-----
From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com]On
Behalf Of Abouel Leil, Tarek M. Ph.D.
Sent: Tuesday, November 21, 2006 10:37 AM
To: nmusers_at_globomaxnm.com
Subject: [NMusers] NONMEM Modeling of Plasma + Urine Data



Hello,

I am trying to simultaneously model the PK of a drug and its metabolite
using NONMEM. I have plasma observations for the parent compound (17-AAG)
and the metabolite (17-AG). I also have 24hr urine collection data for both
compounds. When I tried to model this using ADVAN7 in NONMEM, it stops
almost immediately with the following error:

MONITORING OF SEARCH:

0PRED EXIT CODE = 1


0INDIVIDUAL NO. 1 ID=0.10100000E+03 (WITHIN-INDIVIDUAL) DATA REC NO.
4

 THETA=


  1.43E+04 2.42E+04 8.44E+04 8.96E+04 1.24E+04 2.13E+04 5.00E+04


 NUMERICAL DIFFICULTIES OBTAINING THE SOLUTION.


 THE COEFFICIENT MATRIX IS ALGORITHMICALLY SINGULAR.


0PROGRAM TERMINATED BY OBJ

 MESSAGE ISSUED FROM ESTIMATION STEP

 AT INITIAL OBJ. FUNCTION EVALUATION

1THERE ARE ERROR MESSAGES IN FILE PRDERR


2006.11.20.1820.57

Here is the NONMEM control stream that I am using:

$INPUT ID AMT EVID RATE TIME DV UVOL CMT BW BSA SEX AGE CRCL BR AP AST DOSE

$DATA ..\data.dta IGNORE=#

$SUBROUTINE ADVAN7

$MODEL

   COMP=(CENTRAL, DEFDOSE, DEFOBS)

   COMP=PERIPH

   COMP=METAB

   COMP=("URINE", NODOSE, INITIALOFF)

   COMP=("METABUR", NODOSE, INITIALOFF)

$PK

   TVCL = THETA(1)

   CL = TVCL*EXP(ETA(1))

   TVV = THETA(2)

   V = TVV * EXP(ETA(2))

   K14 = CL/V

   S1 = V

   TVQ = THETA(3)

   Q = TVQ * EXP(ETA(3))

   TVV2 = THETA(4)

   V2 = TVV2 * EXP(ETA(4))

   K12 = Q/V

   K21 = Q/V2

   TVCLM = THETA(5)

   CLM = TVCLM * EXP(ETA(5))

   K13 = CLM/V

   TVCLMO = THETA(6)

   CLMO = TVCLMO * EXP(ETA(6))

   TVV3 = THETA(7)

   V3 = TVV3 * EXP(ETA(7))

   K35 = CLMO/V3

   S3 = V3

   S0=UVOL

$ERROR

   ASY1=0

   IF (CMT.EQ.1) ASY1=1

   ASY2=0

   IF (CMT.EQ.3) ASY2=1

   ASY3=0

   IF (CMT.EQ.4) ASY3=1

   IPRED = F

   W = 1

   IF (F.EQ.0) W=1

   IRES = DV-IPRED

   IWRES = IRES/W

 
Y=IPRED+ASY1*ERR(1)+ASY2*ERR(2)+ASY3*ERR(3)+(1-ASY1)*(1-ASY2)*(1-ASY3)*ERR(4
)


$THETA (0,14300.,) ; TVCL

$THETA (0,24200.,) ; TVV

$THETA (0,84400.,) ; TVQ

$THETA (0,89600.,) ; TVV2

$THETA (0,12400.,) ; TVCLM

$THETA (0,21300.,) ; TVCLMO

$THETA (0,50000.,) ; TVV3

$OMEGA 0.25 ; ETATVCL

$OMEGA 0.25 ; ETATVV

$OMEGA 0.25 ; ETATVQ

$OMEGA 0.25 ; ETATVV2

$OMEGA 0.25 ; ETATVCLM

$OMEGA 0.25 ; ETATVCLMO

$OMEGA 0.25 ; ETATVV3

$SIGMA 100 ; ERRSD17AAG

$SIGMA 100 ; ERRSD17AG

$SIGMA 100 ; ERRSD17AAG URINE

$SIGMA 100 ; ERRSD17AG URINE

$EST METH=0 MAXEVAL=9999 NOABORT POSTHOC PRINT=5 SIGDIGITS=5

$COVARIANCE

The data file looks like this:

#ID AMT EVID RATE TIME DV UVOL CMT
101 31500000 1 31500000 0 0 0 1

101 0 2 0 0 0 0 4
101 0 2 0 0 0 0 5
101 0 0 0 0.5 20 0 3
101 0 0 0 0.5 231 0 1
101 0 0 0 0.92 51 0 3
101 0 0 0 0.92 300 0 1
101 0 0 0 1.08 47 0 3
101 0 0 0 1.08 146 0 1
101 0 0 0 1.25 40 0 3
101 0 0 0 1.25 109 0 1
101 0 0 0 1.5 55 0 3
101 0 0 0 1.5 121 0 1
101 0 0 0 2 42 0 3
101 0 0 0 2 119 0 1
101 0 0 0 3 25 0 3
101 0 0 0 3 75 0 1
101 0 0 0 5 17 0 3
101 0 0 0 5 25 0 1
101 0 0 0 9 0 0 1
101 0 0 0 9 0 0 3
101 0 0 0 17 0 0 1
101 0 0 0 17 0 0 3
101 0 0 0 24 1993.956 904 -4
101 0 0 0 24 609.6032 904 -5


I was able to model the above data without urine observations, so I feel
there must be something wrong with the way I am coding the urine
compartments. I would really appreciate any advice.

Thanks,

Tarek A. Leil, Ph.D.

Department of Oncology, Guggenheim 1311

Mayo Clinic

200 First Street SW

Rochester, MN 55905

ph: 507-538-4227

fax: 507-266-5146

pgr: 08189


Received on Wed Nov 22 2006 - 19:23:38 EST